For instance, in a non-peptide/non-proteinaceous drug such as an anti-inflammatory steroid, the development of a pharmaceutical preparation for nasal administration is desired because of the fact that (1) the topical nasal mucosa can be an objective site of action, (2) rapid action can be expected in the pharmaceutical preparation for nasal administration, (3) on the other hand, the absorption through oral administration is low in some drug, and others.
Further, many of peptide/proteinaceous drugs are not readily absorbed into body mainly because it is readily decomposed by proteolytic enzymes in the gastrointestinal tract when orally administered. Therefore, it is often forced to administer such a drug by injection in order to use it for therapy. Unfortunately, injection imposes burden such as pain, attendance to the hospital, etc., to a patient. Accordingly, it is desired to develop a pharmaceutical preparation for noninvasive administration such as nasal administration which can substitute injection.
Nasal administration, by which a drug is transferred into circulating blood through the nasal mucosa, is being energetically studied as a method for non-injection type administration together with transdermal administration, transocular administration, transrectal administration, transpulmonary administration, etc. Among these non-injection type administration methods, the nasal administration is easy to administer a drug. Moreover, nasal administration is considered to be superior in the absorption of a drug among the non-injection type administration methods since the blood vessel system in the nasal mucous membrane is more developed compared with the skin, the ocular mucous membrane, the rectal mucous membrane, etc. Therefore, a pharmaceutical preparation for nasal administration has been put into practice in some drugs. Further, the transfer of a drug into blood in nasal administration is faster than that in oral administration, and it can be expected that nasal administration has immediate effect similar to injection. On the other hand, the absorption of a drug through the nasal mucosa depends on physical properties such as lipophilicity of the drug and also on the molecular weight, etc. It is pointed out that a drug having a high solubility in water, a drug having a high lipophilicity, a peptide/proteinaceous drug having a large molecular weight, etc., is generally low in absorption trough the nasal mucosa. Under these circumstances, some contrivances to improve the absorption of such a drug through the nasal mucosa has been proposed.
For instance, Suzuki, et al., [Japanese Patent Publication (Examined) 60 (1985)-34925] disclosed a long acting pharmaceutical preparation for nasal cavity comprising a cellulose ether and a drug.
The long acting pharmaceutical preparation for nasal cavity of the patent publication is aimed to allow a drug to adhere on the nasal mucosa and to slowly release the drug over a long period of time. Some of the objects, i.e. the drug is absorbed through the nasal mucosa and the effective amount of the drug is released in a sustained state, have been achieved. However, the main object of a long acting pharmaceutical preparation of said patent is put on the slow releasing of the drug, and accordingly the enhancement of absorption of the drug appears to be not always sufficient. The drugs concretely cited as preferable examples in said patent include an anti-inflammatory steroid, an analgesic anti-inflammatory agent, an antihistaminic agent, a drug having anti-allergic effect, etc., for which the keeping of topical concentration rather than systemic absorption is important.
In a long acting pharmaceutical preparation for nasal cavity of said patent publication, it is assumed that a high pernasal absorption ratio is hardly achieved for a drug having a high solubility in water, a drug having a high lipophilicity or a peptide/proteinaceous drug having a large molecular weight. Under these circumstances, the development of a pharmaceutical preparation for administering such a drug on the nasal mucosa, which can utilize it effectively in terms of curing effect and curing efficiency, is strongly desired.
Nolte, et al., (Hormone Metabolic Research Vol. 22, 170-174, 1990) and Bruice et al., (Diabetic Medicine Vol. 8, 366-370, 1991) reported insulin preparations for nasal administration containing sodium glycolate or sodium taurofusidate as an absorption promoter. However, these absorption promoters have problems in irritation on the nasal mucosa, and the preparations have not been put in practice yet.
On the other hand, Suzuki, et al., [Japanese Patent Publication (Examined), 62 (1987)-42888] disclosed a powdery composition for nasal administration excellent in absorption through the nasal mucosa comprising a polypeptide and a water-absorbing and water-insoluble base material. They reported that the nasal absorption of the polypeptide without using an absorption promoter had been achieved in the composition.
However, even in the composition of the above patent publication, none of the nasal absorption ratios of polypeptides [the area under blood concentration-time curve (AUC) after nasal administration] exceeds 10-20% of AUC in injection. For instance, in Example 4 of the patent publication, the maximum blood concentration of insulin was less than 200 μU/ml when 10 units of insulin had been administered to a rabbit, and it was about 20% of the maximum blood concentration obtained in injection with same amount of insulin. The absorption ratio of the nasal preparation determined from AUC is estimated to be less than 10% of the absorption ratio of injection.
The patent publication describes the combined use of a water-absorbing and water-insoluble base material with a water-absorbing and water-soluble base material in an amount of 0.1-60 wt % based on the water-absorbing and water-insoluble base material, especially preferably 1-50 wt %.
However, concerning the objects and the effects of the combined use, only the slow releasing effect (slow releasability or sustainability) comparing the single use of a water-absorbing and water-insoluble base material is described.
Further, there is no description about the use of a non-peptide/non-proteinaceous drug instead of a polypeptide.
Furthermore, in spite that the patent publication cites a number of water-absorbing and water-insoluble base materials including crystalline cellulose and a number of water-absorbing and water-soluble base materials including hydroxypropyl cellulose, it does not mention at all that a combination of base materials having specific kinds, specific compositions and specific particle sizes among these base materials can provide a powdery composition for nasal administration which can exhibit an excellent maximum blood concentration for a peptide/proteinaceous drug or a non-peptide/non-proteinaceous drug.
Generally, a peptide/proteinaceous drug is expensive, and further when an absorbing ratio is low, its blood concentration tends to vary largely and an expected curing effect is not stably obtained in many cases. Therefore, it is desired to provide a composition of a peptide/proteinaceous drug for nasal administration capable of giving a higher rate of absorption. Further, it is strongly desired to provide a composition for nasal administration which is safe and capable of giving a higher rate of absorption at the same time. Furthermore, it is desired to provide a composition for nasal administration capable of giving a higher maximum blood concentration. The situations are same in a non-peptide/non-proteinaceous drug.
One of the objects of the present invention is to provide a composition for nasal administration excellent in absorption of a drug.
Another object of the present invention is to provide a composition for nasal administration capable of exhibiting high absorption of a drug, especially a higher maximum blood concentration.
A further object of the present invention is to provide a composition for nasal administration capable of exhibiting high absorption, especially a higher maximum blood concentration, even for a drug having a high water solubility, a drug having a high lipophilicity or a peptide/proteinaceous drug having a larger molecular weight.
Still another object of the present invention is to provide a composition for nasal administration capable of exhibiting more excellent absorption, especially capable of exhibiting a higher maximum blood concentration, also for a drug which can exhibit excellent nasal absorption by nature, that is, a drug which is not high in water solubility nor high in lipophilicity, a drug which is a non-peptide/non-proteinaceous drug, etc.
Yet another object of the present invention is to provide a composition for nasal administration which is described in the above objects and at the same time excellent in safety.
The inventors of the present invention have zealously pursued studies for achieving the above-mentioned tasks and completed the present invention by finding that one can provide a new powdery composition for nasal administration excellent in absorption through the nasal mucosa by using a pair of base materials of specific kinds and having a specific composition and by specifying the state of existence of a main drug in the base materials, even for the drug having low absorption through the nasal mucosa or a non-peptide/non-proteinaceous drug.